The skin is the largest organ in the human body and is in a state of constant turnover. This is accomplished by the outward movement of the basal layer keratinocytes at a rate that varies with age, sex, position on the body and other conditions. Psoriasis, an affliction of the epidermis, is a common disorder present in approximately 6.4 million people in the United States according to the National Psoriasis Foundation. The frequency of the disease varies with race, age, skin location and other conditions. The characteristic feature of psoriasis is hyperproliferation of the keratinocytes, first described by Van Scott and Ekel..sup.1 There is evidence of significant shortening of the epidermal cell cycle (36 hours versus 311 hours for normal tissue) in the involved skin of patients with psoriasis. In addition there is a doubling of the proliferative cell population and it appears that in psoriatic skin 100% of the germinative cells of the epidermis enter the growth fraction, compared to 60 to 70% for normal skin of non-psoriatic patients. It is felt that as a result of these changes there is an increase in size and in cohesiveness of corneocytes..sup.2 Transplantation studies of normal and psoriatic human skin to congenitally athymic nude mice have found that, although epidermal proliferation remains above normal in the transplanted psoriatic skin, the absence of clinical lesions (erythema, induration and scaling) suggests that epidermal proliferation does not itself give rise to psoriasis.
The fundamental cellular and metabolic defects underlying psoriasis are not well understood. Endothelial cells, mast cells and fibroblasts have been implicated in the pathogenesis of the disease..sup.3 Granulocytes are present in the spongioform microabscesses that constitute a hallmark of psoriasis and activation of isolated peripheral granulocytes correlates with disease severity.
Dermal fibroblasts are potent producers of cytokines and lipid mediators that may influence epidermal proliferation as well as the inflammatory reaction seen in psoriasis. Studies of the activity of membrane messenger systems have demonstrated that such systems are activated in psoriatic fibroblasts taken from lesional skin. In these studies the activity of membrane bound but not cytosolic phospholipid/Ca dependent protein kinase C (PKC) was significantly elevated..sup.4
Peptide mediators are involved in the inflammatory cascade which takes place in the psoriatic skin. Complement split products, cytokines, interleukins and transforming growth factor alpha are found to be elevated in psoriatic skin..sup.5 They form part of the body's (defective) skin repair mechanism.
The cyclic nucleotides are not thought to be part of the basic molecular aberration in psoriasis, although it is now agreed that two basic alterations in the second messenger systems occur in psoriatic skin: (1) cyclic GMP levels are elevated in psoriatic lesions, and (2) stimulation of epidermal cells with a beta agonist leads to lower levels of cyclic AMP in the epidermis of lesional skin than in normal or uninvolved skin..sup.6
The protease/antiprotease system has also come under scrutiny as increased protease activity has been noted in lesional skin. Proteases have the ability to regulate cell proliferation in other cell systems and can generate inflammatory mediators via the complement cascade..sup.7
Utilization of fatty acids by keratinocytes appears to be fundamental to the development of psoriasis and is of relevance to the present invention. In particular, arachidonic acid and linoleic acid are polyunsaturated fatty acids which appear to be destined for different purposes in keratinocytes. Arachidonic acid is metabolized via the cyclooxygenase pathway predominantly into prostaglandins, such as PGE2, PGF2 Alpha, and PGD2, which modulate normal skin physiological processes at low concentrations and inflammatory reactions at high concentrations. Arachidonic acid is also metabolized via the lipoxygenase pathway into 15-hydroxyeicosatetraenoic acid (15-HETE) and other leukotrienes which function as potent inflammatory mediators. These mediators appear to play a role in producing the abnormalities typical of psoriatic lesions, such as infiltration of epidermal cells and epidermal hyperplasia as well as erythema and induration..sup.8
The lipoxygenase pathway metabolizes linoleic acid into 13-hydroxy-9, 11-octadecadienoic acid (13-HODE). 13-HODE exerts anti-proliferative properties in keratinocytes, possibly via selective suppression of protein kinase C-beta isozyme activity..sup.9
It appears that modulation of the cyclooxygenase and lipoxygenase metabolic pathways may influence psoriasis symptoms. For example, in some patients administration of nonsteroidal antiinflammatory medications (NSAIDS), which are known to inhibit the cyclooxygenase pathway, is associated with the onset or worsening of psoriasis symptoms. It may be that NSAIDS increase the amount of arachidonic acid substrate available to shunt down the lipoxygenase pathway, resulting in increased leukotriene production. By contrast, benoxaprofen, a drug that somewhat selectively blocks the lipoxygenase pathway, has been demonstrated to improve psoriatic symptoms in about 75% of patients studied.
Other findings suggest a possible link between fatty acid metabolism in skin cells and development of psoriasis. Dietary deficiencies of the essential fatty acids linoleic acid and gamma-linoleic acid are associated with increased levels of arachidonic acid and decreased PGE2. Moreover, deficiency of linoleic acid and gamma-linoleic acid has been shown to result in increased DNA synthesis and formation of a scaly dermatosis in some individuals. Also of interest is the finding that human skin fibroblasts preferentially increase linoleic acid incorporation into lipids (80% into phospholipids) and decrease arachidonic acid utilization as they age..sup.10 This may suggest an increased need for linoleic acid (and a heightened sensitivity to a deficiency thereof) as the fibroblasts age. This finding correlates with the clinical progression of psoriasis. Although psoriasis varies from patient to patient, the overall tendency is for the disease to gradually increase in severity as the patient ages.
Although the exact molecular disruption underlying psoriasis remains elusive, recent studies suggest that psoriasis is an immune-mediated disorder. Early and late onset psoriasis has been associated with certain HLA antigens which may help explain the inheritance pattern of the disease. Activated T cells are present in abnormally large quantities in active psoriatic skin. T cell derived cytokines are postulated to be candidates for inducing psoriatic changes as IL-2 therapy for malignancy in psoriatic patients has caused severe psoriatic exacerbation. Some therapies which suppress T cell development, such as administration of cyclosporin or psoralen plus Ultraviolet A (PUVA), have proven effective in clearing psoriasis lesions. While such therapies are effective in treating psoriasis, they also affect other cellular systems so the T cell changes may be but one of a number of factors in the pathogenesis of the disease.
Most current treatments for psoriasis act by regulating the immune system or otherwise attenuating the inflammatory response. Internal medications such as cyclosporin, methotrexate and retinoids all have potentially serious side effects such as liver and kidney damage, nausea, birth defects and increased cancer risk. Other common psoriasis treatments are also undesirable for long-term management of the disease. Extended use of topical corticosteroid creams may cause thinning of the skin, stretch marks and suppression of the patient's own cortisol production. Moreover, psoriatic symptoms tend to recur rapidly after cessation of corticosteroid use. Phototherapy can result in skin aging and increased risk of skin cancer.
The need has therefore arisen for a non-toxic, long-term treatment for psoriasis which does not merely attenuate inflammatory symptoms but endeavours to remedy local cellular nutritional deficiencies underlying the disease.